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T-cell repertoire and HIV infection: Facts and perspectives

Cossarizza, Andrea1,2

Editorial Review

1Department of Biomedical Sciences, Section of General Pathology, University of Modena School of Medicine, Modena, Italy.

2Requests for reprints to: Dr Andrea Cossarizza, Department of Biomedical Sciences, Section of General Pathology, via Campi 287, 41100 Modena, Italy.

Sponsorship: This work has been partially supported by Istituto Superiore di Sanità, Rome (Italy): IX Progetto di Ricerche sull'AIDS, grants Nos 9402-09.

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The T-cell receptor and T-cell repertoire

Cellular immunity is conferred in the large part by lymphocytes which mature in the thymus and recognize, by way of a specific clonotypic receptor, non-self molecules that have been processed into peptides and presented by major histocompatibility complex (MHC) class I or class II molecules. The selection from the pool of genomic regions codifying for T-cell receptor (TCR) genes allows the potential expression of approximately 1015 different TCR, which can, in principle, recognize a similar large number of antigens [1–3]. However, T lymphocytes actually utilize only a small portion of this repertoire. During their intrathymic maturation, T cells undergo a series of events that select them in a positive or negative manner, provoking their expansion or deletion, respectively [4,5]. The ultimate result of these phenomena is that every day the thymus gland produces, chooses and releases cells which have to colonize the periphery, encounter a great variety of antigens and neutralize those dangerous for the host [6–9].

The antigen-specific TCR present on most peripheral blood T cells is a disulphide-linked, heterodimeric, transmembrane glycoprotein composed of an α and a β chain [10–12]; it is clonally distributed on T lymphocytes in association with the CD3 complex [13]. These polypeptides are encoded in the germline by various dispersed gene segments comprising variable (V), diversity (D) (for the β chain gene), joining (J), and constant (C) gene segments. During T-cell development, functional α and β genes are formed by DNA rearrangements that generate V-(D)-J genes which are then linked to a C-region gene segment by RNA splicing, following transcription [14,15]. Diversity in the TCR is generated by random utilization of a large number of germline V, D and J segments; by junctional variations generated between gene segments during the joining process; by random insertion of P- and N-nucleotides junctions between the V, D and J segments of the β chain and the V and J gene segments of α chains; or by combinatorial association of α and β chains. In contrast with B cells, T lymphocytes are not supposed to undergo any process of hypersomatic mutation [16]. The final goal of all these processes is to avoid the generation of autoreactive cells during ontogeny outside the selective environment of the thymus, where such cells are eliminated by the triggering of genes causing programmed cell death or apoptosis [17].

Both chains play a major role in shaping the peripheral T-cell repertoire and in responding to different antigens. The β chain is also fundamental for both positive and negative selections [18–20]. In humans, at least 57 V gene segments are used to form β chains, and they can be grouped into 24 families, based upon having 75% or greater sequence homology [21].

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Antigens, superantigens and virus

Conventional antigens are recognized by T lymphocytes after processing by ‘professional’ antigen-presenting cells and their presentation in association with MHC molecules [1,22]. Antigens degraded in the cytoplasm, mainly of endogenous origin, are bound to MHC class I molecules and presented to CD8+ T cells. Those processed in acidified vesicles, mainly exogenous, are bound to class II and recognized by CD4+ T lymphocytes. MHC class I molecules consist of two polypeptide chains, an α or heavy chain which has three domains (α1, α2 and α3) and a smaller, noncovalently associated chain, the β2-microglobulin (β2-μ), which has one domain. The α3 domain and that of β2-μ have a folded structure that is very similar to that of an immunoglobulin domain, whereas the α1 and α2 domains pair to generate a long cleft, or groove, that is the site at which peptide antigens bind to the MHC molecule. MHC class II molecules are formed by two chains, α and β, which form a structure very similar to that of class I. However, in contrast with MHC class I, the two domains forming the peptide-binding cleft (α1 and β1) are given by different chains. Another important difference is that the ends of the peptide-binding cleft are more open in MHC class II molecules. As a consequence, the ends of a peptide bound to class I are buried within the molecule, whereas the ends of peptides bound to class II are not. In both cases, however, peptides are stably bound to MHC molecules so that the upper surface of the molecule, i.e., the surface recognized by the TCR, is composed of residues of the MHC molecule and the peptide (for a more detailed description of the interactions among MHC, peptide and TCR, see [23,24]).

Molecules exist that have a distinctive mode of binding the TCR, allowing them to stimulate a very large number of T lymphocytes. They are produced by many different micro-organisms and pathogens, including viruses, bacteria and mycoplasms, and are called ‘superantigens’ (SAg) [25,26]. Bacteria produce secreted proteins, whereas rabies virus carries them in the infectious particle as nuclear capsid proteins; retroviruses can produce them only after the integration of proviral DNA into the genome of the host. All of them share the ability to bind directly MHC class II molecules without being previously processed, and a typical bacterial toxin with SAg properties has about 3600 binding sites per cell, with an apparent Kd of 8 × 10−7 M [27–31]. Instead of binding in the groove of MHC molecule, SAg bind to the upper surface of both the MHC class II molecule and the Vβ region of the TCR (Fig. 1) [32,33]. Many of them show a different binding capacity to class II isotypes [34–36]. As SAg binding occurs away from the complementarity determining region (i.e., the part of the TCR-MHC complex usually containing the processed antigen [37]), the V region of the α chain and the DJ junction of the β chain have neglegible importance [38]. Each SAg can bind and activate all the lymphocytes bearing a given Vβ part of the TCR [39], but the same SAg can bind more than one Vβ family, triggering a consistent percentage of mature T cells (up to 20–30%). Thus, if conventional peptides normally stimulate fewer than one in 10 000 T lymphocytes, SAg can activate as many as one in five T cells [28], causing oligoclonal ‘expansions’ of cells with the same Vβ TCR. Analysing peripheral blood, most clinical immunologists consider an expansion the presence of cells with a given Vβ-TCR that exceeds the mean + 3 SD of the values of that family in normal donors.

Fig. 1.

Fig. 1.

SAg-induced activation is not specific and does not confer adaptive immunity. Sometimes it is more dangerous than beneficial for the host, causing massive production of cytokines by CD4+ lymphocytes. A typical example of the effect of a SAg stimulation is that occurring during food poisoning, one-quarter of which is caused by staphylococcal enterotoxins, at least in the United States [40]. Other toxins can provoke different pathologies, such as toxic shock syndrome, scalded skin syndrome, shock, rheumatic fever, scarlet fever and arthritis [41–45]. SAg can also induce profound deletions in the mature T-cell compartment, inducing apoptosis in immature precursors which bind to them [46,47]. The elimination of self-SAg-reactive T cells during intrathymic education plays an important role not only in shaping the T-cell repertoire [48], but also in influencing the dominant Vβ elements used in responses to conventional peptides [49]. The lack of a given Vβ family could also have a positive value by protecting against the effects of bacterial toxins [50], or by decreasing the susceptibility to a variety of autoimmune disorders where a dominant Vβ association exist [51–58].

‘Endogenous’ SAg are encoded within the genome of the host. In mice, they were originally designated ‘minor lymphocyte stimulating’ (Mls) antigens because, even if they are not protein of the MHC, they are capable of inducing a strong primary T-cell response when T cells from a strain lacking the SAg gene were stimulated by B-cells from MHC-identical mice which had the gene [59]. Mls proteins bind to certain Vβ-TCR, causing immature T-cells apoptosis [60]. Expression of endogenous SAg in mice strongly influences the repertoire as, for example, Mls-1a mice have virtually no Vβ6+, Vβ8.1+ and Vβ9+ T cells [61]. Endogenous SAg may only be nothing more than viral products. More than 60 years ago it was known that in mice a carcinogenic factor could be maternally transmitted and present in the milk [62]. Subsequently, it was identified as a virus, the mouse mammary tumor virus (MMTV) [63], more precisely a type B retrovirus which can be isolated in large quantities (up to 1012 particles/ml) in the milk of infected animals [64]. Such virus can also be transmitted as endogenous proviral DNA that has integrated into germ cells, following Mendelian inheritance patterns. In C3H/HeJ mice, Marrack et al. reported for the first time that MMTV produces a self-SAg (in this case encoded by a retroviral integrant) which is capable of stimulating Vβ14+ or Vβ15+ peripheral T lymphocytes [65]. A consistent part of the action of endogenous SAg is exerted within the thymus, during the process of maturation and selection of T lymphocytes. It produces the same effects as the administration of a given SAg during the development of the immune system, i.e., apoptosis of the cells capable of binding that particular molecule. In other words, immature thymocytes that bind to a SAg trigger the programmed cell death programme, with the consequent possible loss of an entire Vβ family. If a response to a pathogen is mostly restricted to a single Vβ family, the immune system can become non-responsive to that pathogen. However, although several efforts have been made to identify the presence and/or the activity of endogenous SAg in humans, their role is still a matter of debate [66].

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A role for human leukocyte antigen during HIV infection?

In humans, evolutionary pressure coming from an enormous variety of antigens of infectious origin has provoked, in several generations, a balance in the frequency of the highly polymorphic alleles of the MHC. Populations of a given geographical area may have selected a particular, advantageous set of MHC molecules, or ‘haplotype’, which present to the immune system certain antigens in an optimal manner. For example, a large case-control study of malaria in West African children showed that an HLA class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, were independently associated with protection from severe malaria: the presence of such alleles was as effective as the sickle-cell haemoglobin variant [67,68].

If, in general, the extraordinary polymorphism of MHC genes has evolved primarily through natural selection by infectious pathogens [69], then, when a new virus such as HIV affects a virgin population, a selective process could be initiated. In simple terms, as an equilibrium between virus and hosts must be reached, those individuals who have a particular haplotype could respond more efficiently, whereas those with another haplotype could experience an unfavourable course of infection. Thus, since the beginning of the AIDS epidemic, researchers have analysed the relationships between host HLA type and the immune response to HIV-1, studying a variety of cohorts, ‘genetic models’ such as monozygotic twins, and individuals who are resistant to HIV infection notwithstanding multiple exposures, such as women prostitutes in Nairobi [70–73]. Some studies have described an association between particular haplotypes and disease progression (e.g., A1-B8-DR3) or resistance to progression (e.g., B27 or DRB1*0702-DQA1*0201), or have reported the increased frequencies of some alleles in homosexual men with Kaposi's sarcoma (B35, −C4, −DR1, and −DQ1) [70,74–79]. Thus, several not mutually exclusive theories have been put forward to explain such associations [80]. First, the way in which different peptides derived from key viral antigens are presented by HLA molecules to T cells is important. This could be the strategy used by the immune system of repeatedly-exposed but HIV-seronegative female Gambian prostitutes with HLA-B35, whose cytotoxic T lymphocytes (CTL) had a vigorous activity against four HIV-1 and HIV-2 cross-reactive peptide epitopes [81]. Second, HLA molecules could be simply a marker for other unknown genes that confer protection or susceptibility. Third, viral peptides could contain sequences similar to HLA that can elicit a sort of autoimmune response which can deplete uninfected T cells. However, a complete review of the papers published in the period 1982–1993 indicates that, even if a significant association was found between a given haplotype and AIDS progression [82], the question of whether and how HLA genes influence susceptibility to HIV infection and its progression remains unanswered. Moreover, the lack of systematic studies addressing this topic must be underlined [83].

It is only recently that immunogeneticists identified the role of other molecules whose genes map within the MHC complex, i.e., the ‘transporters associated with antigen processing’ (TAP)-1 and -2 [84–86]. These proteins, which belong to the ATP-binding cassette transporter family, are expressed in a diversity of cells, from prokaryotic to mammalian, and show specificity for a variety of different substrates [87,88]. TAP proteins play a crucial role either in transporting peptides from the cytosol to the lumen of the endoplasmic reticulum (ER), where they bind MHC class I molecules and complete their folding, or in exporting the class I molecule/peptide complex that is delivered to the cell surface (Fig. 2). Note that these phenomena occur after the dissociation of calnexin, a 90 kDa chaperone of the ER that binds to newly-synthetized α chain, enhances its folding and assembly, reduces its degradation and facilitates the formation of the α chain/β2-μ complex [89]. Interestingly, mutations or polymorphisms of TAP genes can modify antigen presentation [90–92], and a possible role of these molecules in HIV infection has been proposed. In a seminal paper, Kaslow et al. treated the complex problem of the role of HLA in HIV infection in a more sophisticated way than the simple associations described in several reports [93].

Fig. 2.

Fig. 2.

Molecular and serological techniques were used to identify products of HLA class I and II as well as of TAP genes in a large cohort of HIV-1 seroconverter men, and three possible patterns have been described. Those individuals belonging to the first, carry the B37 or B49 HLA gene products and, independently from TAP variants, showed faster progression. Men of the second pattern may or may not have a specific TAP2 variant in combination with one of several class I alleles (A24, A28, A29, or B60 with either TAP2.1 or TAP2.3, and A23 without TAP2.3) and experienced more rapid progression. Finally, combinations of TAP1.2 variant with one of four particular class II haplotypes (DRB1*0401–DQA1*0300–DQB1*0301, DRB1*1200–DQA1*0501–DQB1*0301, DRB1*1300–DQA1*0102–DQB1*0604 or DRB1*1400–DQA1*0101–DQB*0503) was also associated with rapid progression to AIDS. Thus, several genetically-independent class I alleles, class II haplotypes or TAP variants can influence the period between the first infection with HIV-1 and the onset of AIDS, and these findings indicate that HLA genes, their combinations rather than single genes, are crucial in the immunopathogenesis of HIV-1 infection.

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Is the T-cell repertoire affected by HIV, and when?

Techniques for analysing T-cell repertoire

The T-cell repertoire can be studied by flow cytometry as monoclonal antibodies (MAb) exist that recognize different Vβ gene products. Flow cytometry offers several advantages, including, first, the possibility of separately analysing the repertoire on CD4+ and CD8+ T lymphocytes. This approach revealed that these subpopulations utilize a different repertoire [94,95], and thus are likely to undergo different mechanisms of intrathymic selection. Secondly, there is the possibility of performing functional studies within a given Vβ family and thirdly sorting cells to obtain purified populations. Additional advantanges are the rapidity of the assays, their accuracy, the easiness of most techniques, of the software that assists flow cytometers, and their sensitivity, which is essential to identify also rare cells. The main disadvantages are the lack of a complete panel of antibodies for all of the Vβ families — about 60% of the repertoire is covered — and the cost of some instruments and MAb, which is sometimes unreasonably out of proportion.

Molecular biology techniques based upon the polymerase chain reaction (PCR) are widely used. The cell population must first be stimulated with a polyclonal mitogen, then cells are collected, and mRNA is extracted, reverse-transcribed and amplified with primers specific for each Vβ family. Finally, mRNA can be quantified. However, PCR does not permit investigators to exactly quantify the use of individual TCR genes, especially because, i) each primer is rather unique in amplifying its specific product; ii) individual T cells express different amounts of TCR mRNA; and iii) lymphocytes must be activated in order to obtain reasonable amounts of mRNA, and the activation depends upon many factors, including the initial state of the cell and the clinical stage of HIV-1 infection [55,96–99]. All these confounding variables suggest that RNA-based assays do not always reflect the percentage of T cells in each family, and the correlations between flow cytometric and PCR data are not always optimal [100].

Additional molecular biology strategies can be used to investigate the repertoire in more detail, and, in particular, to demonstrate the clonality of an expansion within a given T-cell population, such as the sequencing of the restricted junctional diversity within a given Vβ family, after PCR amplification [101]. For the same purpose, researchers can investigate the hypervariable regions present within the variable region of the T-cell receptor chains, and in particular the length of the third complementary determining region (CDR3) [102].

The clonality can also be demonstrated by the heteroduplex analysis. In this case, cDNA obtained from peripheral blood lymphocytes is amplified with primers for different Vβ families. The product is denatured and renatured to allow random reannealing of the strands and the heteroduplexes carrying mismatched junctional sequences can be separated from the homoduplexes on polyacrylamide gels. Whenever one or more T-cell clones are expanded to over 10% of the polyclonal background, discrete homo- and heteroduplex bands appear [103,104]. This technique has several advantages over standard Southern blot because it is simple, rapid, not radioactive, and more sensitive than other PCR-based procedures. In particular, the cases with uncertain or contradictory patterns can be solved by the heteroduplex analysis, showing homoduplex or heteroduplex bands of clonal nature. This method has been applied to study the clonality of T cells in several physiopathological conditions, including the process of ageing, rheumatoid arthritis, celiac disease, or the response to allergens in asthma [103,105,106].

Functional studies on TCR can utilize bacterial SAg such as Staphylococcus aureus enterotoxins, which stimulate one or a few Vβ families [39,107]. Investigators evaluate the proliferative capability of T cells, which can be easily assessed by a variety of methods [108,109]. Another approach is that of analysing the capability of T lymphocytes to kill target cells (usually the murine line P815) after the stimulation with anti-Vβ MAb, in an assay called redirected killing (RDK).

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The first positive evidence followed by several negative results

Recently, alterations in the T-cell repertoire during HIV infection have been a matter of debate, and contrasting results have been reported (Table 1). By using a semiquantitative PCR method, Imberti et al. showed that in HIV-infected patients the Vβ repertoire was more restricted than that found in normal controls, whereas the corresponding Vα repertoires were identical [110]. Several families (Vβ14 to Vβ20) appeared to be consistently deleted, suggesting that HIV infection could result in death of targeted T-cell populations. This report suggested that HIV infection could result in death of targeted T cell populations. At the cellular level, Laurence et al. presented evidence that human CD4+ cell lines expressing selected Vβ gene products can all be infected in vitro with HIV-1, but give markedly different titres of virion production [111]. Dalgleish et al. found a significant increase in peripheral expression of Vβ5.3 subfamily in HIV-positive subjects [112], whereas Bansal et al. reported a significant reduction in Vβ5.1, Vβ5.2, Vβ12 and Vα2 gene products in homosexuals males with AIDS [113]. Hodara et al. described the overexpression of Vβ2 in CD4+ but not in CD8+ from AIDS patients, together with deletion or underexpression of other families (Vβ9 to Vβ20) in CD4+ but not in CD8+ T cells [114]. Dadaglio et al. found specific anergy of Vβ8+ T cells from infected individuals [115]; a selective depletion of CD4+, Vβ19+ cells was attributed to SAg properties of the virus by McCoy et al. [116]. Variations in the structure of gp160 or gp120 have been reported to preferentially stimulate certain families [117,118]. Different changes in peripheral lymphocytes and lymph nodes from HIV-positive patients, with recurrent alterations in Vβ5.2/5.3, Vβ12 and Vβ21, have also been reported [119], as well as other preferential usages, expansions or deletions of different Vβ families [120–122]. Vβ12 was found expanded also in CD8+ cells from four out of five HIV-positive children, and in one out of six seronegative children born to seropositive mothers [123].

Table 1

Table 1

Table 1

Table 1

According to one hypothesis, HIV might act as a viral SAg, provoking deletions of certain Vβ families or expansions of others [124], and the lack of responsiveness to a variety of agents could find one explanation. If the response to a given pathogen is mostly due to the activity of a particular Vβ family, its deletion causes an immunological ‘hole’. However, no data are available on possible relationships between specific holes and the presence of certain pathogens. Moreover, according to the theory of T-cell homeostasis (suggesting that the immune system is able to regulate the number of T cells, which must remain stable) [125,126], each Vβ family expansion provokes restriction of the repertoire because it occupies part of the fixed T-cell compartment.

Other reports described opposite results. In fact, no preferential deletion of any particular Vβ subsets was found by Posnett et al. in AIDS patients [127], or by Boyer et al. in patients with CD4+ cell counts of < 200 × 106/l [128]. Soudeyns et al. [120] and Rebai et al. [129], analysed the Vβ repertoire in monozygotic twins, discordant for HIV-1 infection, and found that most of the Vβs were left unperturbed, whereas several, unspecific alterations in different Vβ segments were observed. Nisini et al. analysed the responsiveness to SAg in two sets of monozygotic twins, discordant for HIV infection [130], and found no major alterations in the proliferative response to SAg.

No functional alterations were reported by Eylar et al. in HIV-positive Hispanic people with AIDS [131]. Bahadoran et al. studied the repertoire in HIV-infected infants born to seropositive mothers [132], and reported no selective Vβ deletion, even when the CD4+ subset was globally depleted. Random Vβ depletions were reported by Boldt Houle et al. [133], and generalized, unspecific effects of HIV infection on the repertoire by Grant et al. [134]. No selective changes were reported by De Paoli et al., who found, expansions among CD8+ T cells, however, in a small percentage of the HIV-positive donors studied [135].

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What happens in a primary infection?

These controversial data were obtained from patients in whom the virus was present for several years, but a few studies have been performed on subjects during primary infection. Pantaleo et al. reported patterns of the repertoire in total T cells during acute HIV syndrome in six patients. They found no deletion of any Vβ family, and a predominant Vβ usage in CD8+ T cells from four patients [101]. The significant presence of specific anti-Env cytotoxic T lymphocytes (CTL) among the expanded families indicated that such expansions were driven by HIV antigens and not due to SAg properties, in accord with observations describing monoclonal or oligoclonal expansions of HIV-specific CTL in a seropositive subject [136].

When the repertoire was studied separately on CD4+ and CD8+ T cells, no major, nor characteristic deletions of Vβ families were found among these subpopulations [109]. Expansions among CD8+ T cells were found in three out of eight patients, but also in two out of 12 seronegative controls [109]. Such frequencies were similar to those reported in studies on the age-related changes in Vβ-TCR among CD8+ T cells of normal donors [137,138]. The expansions were temporary; in a few weeks the expanded Vβ families returned to normal values (unpublished data). Finally, the stimulation with bacterial SAg demonstrated that the repertoire was functionally intact.

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Are CD8+ T cells the only ones capable of undergoing expansion?

CTL are a fundamental line of defence against many viruses, including HIV. It was first shown that specific CD8+ T cells are capable of limiting, in vitro, HIV-1 replication [139], and CTL specific for HIV-1 proteins have been demonstrated early during the course of infection, before the production of antibodies [140]. HIV has elaborated several strategies to escape immune recognition, which include its dramatic capability to produce billions of new particles every day [141–143], as well as to mutate continuously, changing the epitopes recognized by CTL [144,145], and acquiring resistance to antiviral drugs [146]. If the first response to the virus is oligoclonal, likely because upon entry HIV is highly homogeneous [147,148], the selection and rapid diversification of HIV strains may result in the accumulation of variants which broaden the immune response, so that, 1 month after primary infection, the pattern of viral proteins that CTL can recognize is large [149]. In a pivotal paper, Cheynier et al. described the T-cell repertoire usage in the spleen of infected individuals [150]. Recognizing a dominant Vβ rearrangement as a marker for HIV-specific CTL, it was shown that these cells are present around the splenic white pulps, suggesting that in these sites replication of the virus within CD4+ lymphocytes and elimination of infected cells by anti-HIV CTL occurred simultaneously. Moreover, progeny deriving from a founder viral genome would reinfect neighbouring cells, and generate variants of the founder sequence. The analysis of the T-cell repertoire in different parts of the same organ provided evidence that white pulps represented islands of restricted and specialized T-cell function, and did not communicate with each other. In other words, in each island the T cells present were recruited by way of local presentation of different, mutated viral antigens.

Certainly, the higher the number of antigens that must be recognized, the lower is the efficacy of the response. Moreover, the first encounter with HIV can provoke a massive activation of CTL which rapidly undergo apoptosis [151,152]. This process is similar to that present in other viral infections, and is likely to be nonspecific and due to pro-inflammatory cytokines [153–155]. Patients experiencing an acute syndrome have a poor prognosis [156,157], suggesting that the massive activation of CTL favours the virus. In any case, the temporal association of increases in viral load and concomitant decreases in CTL activity, the different functional capacities of CTL during different phases of infection, and observations that a strong anti-HIV CTL activity is present in HIV-exposed but uninfected individuals, suggest that an adequate, HIV-specific cytotoxic activity may have an overall beneficial impact on disease progression [158,159]. The decrease of HIV plasma levels after primary infection, as well as the maintenance of stable levels of viremia and of peripheral CD4+ cells can thus be considered not only good prognostic factors, but also the best indicators of antiviral CTL response. The questions remain unanswered whether and which Vβ expansions among CD8+ T cells had a similar meaning.

Even if few data exist in humans concerning the presence of Vβ expansions within CD4+ T cells, perturbations in the T-cell repertoire do not seem to be a unique characteristic of CD8+ T lymphocytes. In seronegative donors of far advanced age and healthy centenarians, CD4+ lymphocytes can undergo oligoclonal expansions, and thus give origin to changes in the repertoire [138]. Studying nine monozygotic twin pairs, in which one member was HIV-positive, Rebai et al. reported the increased expression of Vβ21 in CD4+ cells from one infected donor [129]. Ramzaoui et al. described the presence of Vβ alterations among CD4+ T cells in CDC stage II patients [160]. By using PCR techniques, Roglic et al. found frequent alterations (either expansions or deletions) of the repertoire among peripheral CD4+ lymphocytes from HIV patients, which were inversely proportional to their CD4 count [161]. Paganelli et al. observed a high frequency of clonal expansions in subjects with asymptomatic HIV-infection, irrespective of its duration, and expansions occurred more often among CD4+ than CD8+ T cells (personal communication). Interestingly, in this case many patients were classified ‘long-term nonprogressors’. We recently followed for some months a small group of patients who presented with acute HIV-syndrome (described in [109]) and, surprisingly, we found that a few weeks after the primary infection some of them presented substantial but temporary Vβ expansions within CD4+ population (unpublished data). The expanded Vβ families were different from those found among CD8+ T lymphocytes during the acute syndrome.

On the whole, these findings are quite intriguing, and it would be important to ascertain the nature and functional meaning of the expanded families among CD4+ T cells. In particular, it will be interesting to ascertain whether such expansions are antigen- or SAg-driven, and whether these CD4+ T cells are able to exert cytotoxicity, possibly by way of molecules such as CD95L [162].

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Conclusions and perspectives

The controversial, available data are far from being exhaustive, as indicated in Fig. 3. According to some authors, alterations in T-cell repertoire are neither present in acute nor in ‘chronic’ infection, and HIV is not an SAg. A striking similarity, due to the lack of changes in the repertoire, thus exists with other viral infections, such as hepatitis C [163]. According to others, alterations are present later because HIV might require some time to act as an SAg. Finally, antigendependent Vβ expansions may be present in HIV infection, especially in the primary response, as in other ‘regular’ immune responses, such as those present during acute infectious mononucleosis [164].

Fig. 3.

Fig. 3.

Recently, it has been proposed that three major patterns in the type of Vβ expansions exist in acute HIV syndrome [165]: first, a major expansion (10-fold higher than the lowest value detected over time) in a single Vβ family; secondly, a moderate expansion (up to sixfold) in one or two families; thirdly, minimal expansions (up to twofold) in one or multiple Vβ, or no expansions at all. In the first months after infection, patients with ‘type 3’ expansions seem to have a more favourable clinical course and higher levels of circulating CD4+ T cells than the others [166]. Further studies are needed to find out whether the type of expansions present during the primary infection could correlate with the overall immune response, and represent a prognostic marker for the entire course of the disease. The follow-up of these subjects and of patients with other clinical responses to HIV will help in clarifying this point. However, as only a small part (∼2%) of lymphocytes are usually present in the peripheral blood, investigations on the repertoire of circulating cells could not give adequate information. Analysis on local, regional responses, for example in lymph nodes or tonsils, could be more useful to identify the engagement of T cells, and eventual preferential uses of their repertoire. Investigations in different animal models, such as non-human primates or immunodeficient mice reconstituted with human cells, are urgently needed to clarify this point.

Clearly, the sometimes dramatic differences in the many results previously described cannot be ascribed to trivial technical problems, use of different techniques, nor differences in populations under investigation. It would be interesting to establish quality control studies in which the same samples are analysed by different laboratories that have been coordinated internationally. Although the fervour has sparked intense activity, conflicts must be resolved.

In conclusion, to prove at the clinical level the utility of the classification of Vβ expansions described above, the number of cases in whom the T-cell repertoire is analysed must be improved and multicentric investigations are necessary. Longitudinal analysis is required to prove the existence of correlations between the course of HIV infection and events that characterize the initial immune response.

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The author gratefully acknowledges Drs C. Franceschi, B. De Rienzo and C. Mussini (University of Modena, Italy), R. Paganelli (University of Rome, ‘La Sapienza') and E. L. Cooper (University of California at Los Angeles, USA) for helpful discussions, communication of unpublished data and critical reading of the manuscript.

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        HIV; AIDS; T cell receptor; T cell repertoire; Vβ families; Acute HIV syndrome

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